tbuckley/cabot-search huggingface dataset:
The critical role of histone modifications in lung adenocarcinoma based on novel molecular subtypes.
Authors: Bo Wang, Lianbin Zhang, Wei Tang, Jianqing Deng, Tianhao Mu
Journal: Journal of Clinical Oncology (2022)

e20510 Background: Studies revealed the pathogenesis and exploring the treatment of lung adenocarcinoma (LUAD), but overall survival (OS) of LUAD patients still remains low in the recent years. Methods: This study analyzed the relationship between gene expression and histone modifications, and discussed the prognostic value of these findings in patients with LUAD. Four types of histone modifications including H3K9me3, H3K27me3, H3K27ac and H3K4me3 were included. Promoters and enhancers in protein coding genes (PCGs) were selected as targeted analyzing regions. Unsupervised consensus clustering was performed to identify molecular subtypes. Cox regression analysis and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model. Results: A large number of epigenetic abnormal genes in lung adenocarcinoma were found by comparing the histone modifications and methylation regions on the elements including. We identified 699 epigenetic dysregulated genes specific to LUAD. Finally, based on these epi-PCGs, we constructed three molecular types of LUAD and identified 5 epi-PCGs as prognostic markers for LUAD patients. Conclusions: Our research provided a better understanding that the abnormal epigenetic regulation of PCG expression contributes a lot for the progress of gene regulation in LUAD. These novel molecular subtypes and the prognostic model could serve as guiders to assist decision-makings for LUAD treatment.
Small molecule-mediated rapid maturation of human induced pluripotent stem cell derived cardiomyocytes
Authors: N Chirico, E L Kessler, RGC Maas, J Fang, J Qin, I Dokter, S Ciccone, T Saric, JW Buikema, Z Lei, P Doevendans, JPG Sluijter, A Van Mil
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Gravitation Program “Materials Driven Regeneration” by the Netherlands Organization for Scientific Research (RegmedXB #024.003.013) and the Marie Skłodowska-Curie Actions (Grant agreement RESCUE #801540). The EU-funded project BRAV3 (H2020, ID:874827) Background Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature human primary cardiomyocytes: the ability to use fatty acids as an energy source, high mitochondrial mass, increased nuclei polyploidism, synchronized electrical conduction, and forceful contractions. Instead, their phenotype is similar to immature cardiomyocytes in the late fetal stage. This immaturity represents a bottleneck to their application in 1) disease modeling – as most cardiac (genetic) diseases have a middle-age onset – and 2) clinical use, where integration and functional coupling are key. So far, the mainly used methods to enhance iPSC-CM maturation include prolonged time-in-culture, 3D culture, cyclic mechanical stretch, and electrical stimulation with specialized media. However, these protocols are laborious, costly, and not easily scalable. Methods In this study, we developed a simple, low cost, and rapid protocol using two peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A/PGC-1α) activating small molecules: Asiatic Acid (AA) and GW501516 (GW) to promote cardiomyocyte maturity by inducing a metabolic switch to fatty acid utilization and increased mitochondrial biogenesis. Results Monolayers of iPSC-CMs were incubated with AA and GW every other day for 10 days resulting in increased expression of fatty acid-metabolism-related genes (5 and 10-fold increase in CPT1B gene expression, respectively), mitochondria biogenesis (protein expression of ATP5A) and fusion (50 and 100-fold increase in OPA1 gene expression, respectively). In addition, AA treated iPSC-CMs responded in the seahorse mitochondria stress test more rapidly to an artificial increase in mitochondrial activity and showed a higher flexibility in substrate utilization in the seahorse stress test. A more mature electrophysiological functionality was shown by increased ion channel gene expression (KCNA4, SCN5A, GJA1, CACNA1C, and SCN1B) and enhanced synchronous contraction in treated samples. Moreover, maturation was further shown by increased sarcomeric gene expression (5 and 7-fold increase in TNNI3 in AA and GW respectively) and nuclear polyploidism (&amp;gt;4N fold 2.16 and 1.48-fold increase in AA and GW respectively). Conclusions Collectively, these findings show that AA and GW trigger a metabolic switch and induce extensive maturation of iPSC-CMs, providing a rapid and cost-effective method to obtain iPSC-CMs that more closely resemble their adult counterparts.
Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial
Authors: Hugh Montgomery, F D Richard Hobbs, Francisco Padilla, Douglas Arbetter, Alison Templeton, Seth Seegobin, Kenneth Kim, Jesus Abraham Simón Campos, Rosalinda H Arends, Bryan H Brodek, Dennis Brooks, Pedro Garbes, Julieta Jimenez, Gavin C K W Koh, Kelly W Padilla, Katie Streicher, Rolando M Viani, Vijay Alagappan, Menelas N Pangalos, Mark T Esser
Journal: The Lancet Respiratory Medicine (2022)
Selected Articles from This Issue
Journal: Clinical Cancer Research (2022)

The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in many tumor types, but development of PI3K inhibitors is challenging because of toxicity risks associated with inhibiting multiple PI3K isoforms.AZD8186 is a potent, selective inhibitor of PI3Kb.In a phase I open-label study Choudhury and colleagues evaluated the safety, tolerability, and recommended phase II dose of AZD8186 monotherapy and in combination with abiraterone acetate or vistusertib.Eligible patients had advanced prostate cancer, triple-negative breast cancer, or squamous non-small-cell lung cancer, and patients with other solid tumor types were eligible if they were PTEN-deficient/mutated or PIK3CBmutated/amplified.As monotherapy and in combination, AZD8186 was well tolerated, with few dose-limiting toxicities reported.Both monotherapy and combination therapy showed preliminary evidence of antitumor activity, which merits further assessment in subsequent studies.
Assessing adherence to adjuvant hormone therapy in breast cancer patients in routine clinical practice.
Authors: Natalia Camejo, Cecilia Castillo, Clara Tambasco, Noelia Strazzarino, Nicolás Requena, Silvina Peraza, Anna Boronat, Guadalupe Herrera, Patricia Esperon, Mauricio Cuello Toledo, Gabriel David Krygier
Journal: Journal of Clinical Oncology (2022)

e12532 Background: Adjuvant hormone therapy (HT) in patients with hormone receptor-positive breast cancer (BC) increases overall survival (OS). Adherence to HT in routine clinical practice is still poorly reported. Many BC patients are treated for other diseases and experience polypharmacy. Methods: Objective To assess adherence to HT in routine clinical practice.Materials and Methods: Adjuvant hormone therapy (HT) in patients with hormone receptor-positive breast cancer (BC) increases overall survival (OS). Adherence to HT in routine clinical practice is still poorly reported. Many BC patients are treated for other diseases and experience polypharmacy. Results: A total of 118 patients were included; 65.2% were treated with aromatase inhibitors (AI) and the rest with tamoxifen, with 36% presenting polypharmacy. Treatment adherence was observed in 81% of the patients, and it was associated with age (p=0.03, OR=0.96 for non-adherence), with adherent and non-adherent patients having a median age of 66 and 61.5 years, respectively; however, adherence was not associated with polypharmacy, territory of origin, marital status, living alone, level of education, occupation, or stage. The adherence profile was similar for both drugs, but homemakers and retired women showed greater adherence to AI. Conclusions: Adherence to HT was assessed in real life, with 19% of the patients not adhering to the treatment, despite the known benefit for OS, being a well-tolerated treatment, and being provided free of charge. The most adherent patients were the oldest. The results show the need to investigate the reasons for discontinuing HT, with Pharmacy and Medical Oncology fields combining efforts to develop coordinated strategies and interventions to increase adherence, given the impact that this may have on patients' OS.
Exploring the contribution of mechano-sensing to cardiomyopathy
Authors: A Azad, H Jiang, C Hooper, B Davies, H Watkin, K Gehmlich
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Medical Research Council (MR/V009540/1), Wellcome Trust (201543/B/16/Z) British Heart Foundation (FS/12/40/29712). Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition associated with diastolic dysfunction and sudden cardiac death. Disease genes for HCM are traditionally coding for proteins involved in force generation. More recently, it has emerged that variants in genes coding for proteins involved in biomechanical stress-signalling can also cause HCM. One such protein is filamin C, with proposed mechano-sensing functions in the heart. Within the protein, the immunoglobulin-like domain 20 (Ig20) may play a crucial role in mediating binding to muscle specific ligands. While the mechano-sensing functions of filamin C have been investigated well in skeletal muscle, the underlying cardiac disease mechanisms are not completely understood. Aim This work attempts to provide insights into the role of filamin C in cardiac mechano-sensing and dissect disease pathways leading to HCM in the presence of the FLNC variants in Ig20. Methods Using mass spectrometry, we aimed to provide a detailed analysis of the proteome of mice carrying the filamin C variant, using ventricular tissue samples from 14wk old homozygous mice. Samples were subject to molecular biology technical and underwent subcellular fractionation (n = 6 per genotype) and were investigated by label-free mass spectrometry. Results Utilising whole genome sequencing, a heterozygous FLNC missense variant in Ig20 was identified in a three-generation family affected by HCM. Mice carrying this variant recapitulate molecular features of HCM in the homozygous setting. Three proteins (FLNC, MYH7, MYOT) were found to be upregulated in the myofilament-enriched fraction. Up-regulations of key proteins were found to relocalise towards load-baring sites. Conclusion Our data indicate that changes in filamin C and its binding partners expression and localisation are involved in the pathogenesis of HCM in this mouse model.
Genetic risk assessment in primary care settings: An evaluation of NCCN guidelines.
Authors: Kara J. Milliron, Bailey Hulswit, Amanda Cook, Stacy Fry, Alec Schraeder, Jerry Tippie, Kelly Hall, Lynn A. McCain, David Keren, Lee Schroeder, Sofia Merajver, Elena Martinez Stoffel
Journal: Journal of Clinical Oncology (2022)

10605 Background: Lynch syndrome (LS) and hereditary breast and ovarian cancer (HBOC) have a population prevalence of 1/279 1 and 1/400 2 , respectively. Despite this, &gt;80% of patients referred for cancer genetic counseling report personal or family history of breast cancer 3 . This disparity may be due to increased media attention for HBOC, lower levels of provider awareness of LS, and less discussion of colorectal cancer within families compared to breast cancer 4 . However, potential biases in National Comprehensive Cancer Network (NCCN) criteria for genetics evaluation (GE) have not been studied. This project examined the performance of NCCN guidelines for identifying individuals meeting criteria for GE ascertained through primary care (PC) settings. Methods: Individuals scheduled for routine PC appointments at three Michigan Medicine affiliated practices from 10/24/18 through 1/24/22 were emailed a link to complete an online personal and family history (P/FHx) risk assessment module (INHERET) collecting information about cancer diagnoses (age/cancer type) in 1 st , 2 nd , and 3 rd degree relatives. The module was written at a 4 th grade reading level and could be accessed on any internet-connected device. NCCN guidelines were applied to determine if patients met criteria for GE of HBOC and/or LS. Results: A total of 465 individuals completed the module; nearly one in three (30.6%, 142/465) met NCCN criteria for GE of HBOC or LS. Of those meeting criteria, 132 (92.9%) had no personal history of cancer. The most common indication for GE was HBOC (29.5%, 137/465) and 30 patients (6.5%) met HBOC referral criteria solely based on Ashkenazi Jewish ancestry. Only 17/465 (3.7%) individuals met NCCN criteria for GE of LS. Interestingly, 12/17 (70.6%) who met criteria for GE of LS also met criteria for GE of HBOC. The completion rate was not 100% and cannot be determined; it is not known how many patients were offered the option of completing the module. This limits the study, as ascertainment bias cannot be assessed. Conclusions: Nearly one-third of PC patients who completed the P/FHx module met NCCN criteria for genetic evaluation of HBOC and/or LS. Referrals for HBOC outnumber those for LS, even though LS is just as common 1, 2, 3 . Further evaluation of NCCN criteria is needed to evaluate whether patients may be over-referred for HBOC and/or under-referred for LS. Unfortunately, we were not able to confirm receipt of email invitations or accurately calculate completion rate of the P/FHX risk assessment module, which limited our ability to assess for ascertainment/response bias. [Table: see text]
Tackling healthcare inequities through a social media-based platform to connect solid tumor patients with COVID-19 to clinical trials.
Authors: Yan Leyfman, Samarth Sandeep, Kirk McGregor, Peter Rizk, Carlo Khoury, Chandler H. Park
Journal: Journal of Clinical Oncology (2022)

e18560 Background: COVID-19 has contributed to healthcare inequity amongst minorities and lower socioeconomic populations, while complicating present anti-cancer treatment regimens. Due to their immunocompromised status, cancer patients are at an increased risk of severe SARS-CoV-2 infection. While sentiment analysis via SM has seen vast growth among healthcare professional, deeper connection and management has been lacking. Given the higher usage of SM impressions and the increase in healthcare disparities especially at the intersection of oncology and COVID-19, the aim of this study was to develop a platform that can: (1) show that the relationships highlighted within these tweets can be realized in biomolecular interactions—specifically within the interaction between solid tumors and COVID-19; (2) use SM data to connect patients with clinical trials. Methods: To determine this relationship, ontologies, which are groupings of terms and related identifiers, such as genes, were created for general search terms, utilizing the Human Phenotype Ontology. They were then combined with “COVID-19” and used as search terms in Twitter’s Standard Search tool. The keywords with the most matches were then queried through clinicaltrials.gov and European Bioinformatics Institute’s (EBI) Protein Search Tool to find relevant clinical trials and proteins. Finally, the proteins found by the EBI protein search were run through the SwissModel Tool to find relevant protein structures before being used in binding using Polar+’s Binding Platform from Iff Technologies, which provides K values related to 50% inhibition for each medication or immunotherapy. This produced a set of disease-specific keywords that are related to top tweets, clinical trials, protein structures, and binding concentration values in relevant biomolecular pathways for the keyword set “Tumor COVID-19”. Results: The example shown in Table is produced via our platform, with keywords with tweet numbers greater than 95% of all tweets with connected keywords used. Conclusions: By utilizing SM with highly relevant keywords, this platform can combat healthcare inequity by connecting patients and their tweets to clinical trials and enhance literacy about their medical conditions, while providing a greater understanding of the biomolecular pathways involved.[Table: see text]
Early discontinuation of abiraterone acetate/prednisone (AA/P) in localized prostate cancer.
Authors: Samia Asif, Makayla Schissel, Benjamin A. Teply
Journal: Journal of Clinical Oncology (2022)

e17003 Background: Data from STAMPEDE trial supporting systemic therapy intensification with long course AA/P was first presented in 2017. Overall survival benefit was confirmed in 2021. Our institution proceeded with early adoption of addition of 24 months of AA/P to ADT and radiotherapy (RT) in patients with high-risk localized or regional prostate cancer in 2017. In STAMPEDE, only 17% patients discontinued AA/P prior to completion of planned course. Outside of a clinical trial, whether patients adhere to this intense combination therapy that is associated with toxicities and expense is unknown. We hypothesized that adherence to long course AA/P in real-world practice in definitively treated prostate cancer would be poor. Methods: We performed a retrospective study for patients with clinically localized prostate cancer treated with AA/P combined with standard ADT and RT who had at least 6 months of follow-up data. Primary endpoint was rate of early discontinuation (prior to the 24mo) of AA/P. Secondary outcomes included rates of RT completion and disease recurrence and toxicity of intensive therapy. Reasons for early discontinuation were analyzed. Fisher's Exact, Chi-square analysis and Mann-Whitney tests were used to compare variables. SAS 9.4 was used for statistical analysis. Results: We identified 77 patients who met inclusion criteria, including 2 (2%) with high-risk, 30 (39%) with very high-risk, 19 (25%) with regional risk and 26 (34%) with locally recurrent disease after prostatectomy. AA/P was discontinued in 29 (38%) patients prior to completion of 24mo. Among those with early discontinuation, median duration of AA/P was 12.1 mo [0.1-21.7] and median duration of ADT was 17 mo[3.5-32.2]. Common reasons for early AA/P discontinuation included refractory hypokalemia (n = 4), diarrhea (n = 3), heart failure and fluid retention (n = 2 each) and quality of life deterioration (n = 8). Other reasons included hepatotoxicity, arrhythmia, osteoporotic fracture and financial toxicity (n = 1 each). All patients completed definitive RT. Only 1 of 77 patients had disease recurrence and had discontinued AA/P after 14 mo. A statistically significant association between age at diagnosis and treatment completion was noted(p = 0.01); each 1-year increase in age was associated with 9.4% decrease in odds of completing AA/P. Median age at diagnosis in those completing vs not completing AA/P was 65 vs 71 years. Conclusions: Very high rates of early discontinuation of AA/P were observed among patients with localized prostate cancer receiving definitive RT. Patients were less tolerant of toxicity in adjuvant setting compared to in a clinical trial or advanced disease. Shorter durations of AA/P appeared more acceptable but whether similar benefit is derived with a truncated course of AA/P is unknown. Future studies need to explore an optimal duration of AA/P that will reduce toxicity without compromising survival benefit.
First-line therapy for gastric cancer with bone marrow metastasis and disseminated intravascular coagulation with infusional fluorouracil and weekly docetaxel: A multicenter, phase II clinical trail.
Authors: Xiaohui Zhai, Taiyuan Cao, Shanshan Li, Xiaoru Lin, Jian Xiao
Journal: Journal of Clinical Oncology (2022)

e16004 Background: Gastric cancer (GC) with bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) is a special subtype of gastric cancer which has highly aggressive characteristic and extremely poor prognosis. Case reports showed chemotherapy achieved survival benefit but prospective trial is still urgently needed. Methods: This is a multi-center phase II clinical trial. Infusional fluorouracil of 200mg/m2/day, D1-21 (LD-FU) with docetaxel 25mg/m2, D1,D8,D15 will be administered to chemo-naïve metastatic GC with BMM and DIC every four weeks. The primary endpoint is the hematology response rate (HeRR) defined as the rate of platelet count restored to 100X109/L or higher. The secondary endpoints are time to HeR, duration of HeR, one-month mortality, overall survival, toxicity and the quality of life. Results: Until Feb 1, 2022, 11 gastric cancer patients with BM and DIC were enrolled in this trail and 8 patients reached the hematology response. The HeRR is 72.72%(8/11) and the media time to HeR is 13.5 days (11-20days). The rate of grade 1or to oral mucositis is 36.36%(4/11) and there is no grade 3 or 4 treatment toxicity. Conclusions: This is the first prospective clinical trail to evaluate the safety and efficacy of chemotherapy for advanced GC patients with BMM and DIC and will provide high level evidence to guide clinical practice. Clinical trial information: NCT04547153.